This invention relates to pyrimidine compounds and pharmaceutically acceptable salts, solvates and prodrugs thereof. The present compounds have been found useful in resisting and treating infections in immunocompromised patients. These compounds are also useful as antitumor, antibiotic, antimalarial, antifungal, antiprotozoal, antituberculosis and antiMycobacterium avium agents, and can also be used as synergistic agents when used with sulfonamides. Methods of preparing and using these compounds are also provided.
Various pyrimidine systems, such as the pyrido pyrimidines, pyrrolo pyrimidines and furo pyrimidines, have been studied due to their involvement in the inhibition of dihydrofolate reductase (DHFR) enzyme activity. Because DHFR reduces dihydrofolate to tetrahydrofolate, inhibition of DHFR deprives the cell of. tetrahydrofolate, without which the cell cannot produce 5,10-methylenetetrahydrofolate. 5,10-Methylene-tetrahydrofolate is essential for cell growth. The inhibition of DHFR by the compounds of this invention results in the inhibition of DNA synthesis and leads to cell death.
The pyrimidine derivatives disclosed herein also function as thymidylate synthase (TS) inhibitors. TS, along with DHFR, forms part of the system responsible for the synthesis of deoxythymidylate (dTMP) from deoxyuridylate (dUMP). TS catalyzes the sole de novo synthesis of dTMP from dUMP. Inhibition of TS, therefore, deprives the cell of thymidine, which is an essential constituent of DNA.
The present invention provides pyrimidine compounds, and pharmaceutically acceptable salts, solvates and prodrugs thereof, having the formula (1): 
wherein R is an aryl ring or alkylaryl ring optionally substituted with one or more substituents independently selected from C1-6 alkyl groups, C2-6 alkenyl groups, C2-6 alkynyl groups, C1-6 alkoxy groups, halogens, nitro groups, aryl groups, C1-6 acyl groups, carboxylic acids, carboxylic esters, hydroxyl groups, mercapto groups, polycarbo groups, and p-aroyl-L-glutamate;
wherein Z is S, Se, O, NH, CH2; and
wherein R1 is H or a straight, branched or cyclic alkyl group having up to about six carbons optionally substituted with one or more halogen, hydroxyl or amine groups.
The present invention also provides methods of synthesizing compounds having formula (1). Methods for using these compounds in the treatment of various illnesses are also within the scope of the invention.
More specifically, the invention provides a method of using the pyrimidine derivatives of Formula 1 for therapeutic and prophylactic purposes including employing these compounds to resist and treat secondary infections caused by Pneumocystis carinii, Toxoplasma gondii, Mycobacterium tuberculosis and Mycobacterium avium complex or other organisms in immunocompromised patients. Immunocompromised patients, for example, may be patients with AIDS, or patients undergoing chemotherapy, steroid treatment, and the like; other immunocompromised patients could also be treated according to this invention. In addition, this invention provides methods of using pyrimidine derivatives as antituberculosis, antiMycobacterium avium complex, antibiotic, antimalarial, antifungal and antiprotozoal agents and as synergistic agents with sulfonamides in such patients, although their use in this application may require the use of leucovorin rescue.
This invention also provides methods of using the present pyrimidine derivatives for therapeutic and/or prophylactic purposes as antitumor agents or to otherwise destroy or minimize growth or proliferation of cancerous cells in cancer patients.
It is an aspect of this invention to provide pyrimidine compounds, and pharmaceutically acceptable salts and prodrugs thereof, for substantially inhibiting dihydrofolate reductase enzymes and/or thymidylate synthase enzymes.
It is another aspect of the present invention to provide derivative compounds, and pharmaceutically acceptable salts and prodrugs thereof, having antitumor, antibiotic, antimalarial, antifungal, antiprotozoal, antituberculosis or antiMycobacterium avium activity or synergistic activity with sulfonamides.
It is a further aspect of this invention to provide pyrimidine compounds having activity against secondary infections, such as infections caused by Pneumocystis carinii, Toxoplasma gondii, Mycobacterium tuberculosis and Mycobacterium avium that occur in immunocompromised patients.
It is another aspect of this invention to provide a method of synthesizing the present pyrimidine compounds and their derivatives.
These and other aspects of the invention will be more fully understood from the drawing and the following description of the invention and the claims appended hereto.